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| - Rational Design and Synthesis of Androgen Receptor-Targeted NonsteroidalAnti-Androgen Ligands for the Tumor-Specific Delivery of aDoxorubicin−Formaldehyde Conjugate
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| - The synthesis and preliminary evaluation of a doxorubicin−formaldehyde conjugate tetheredto the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostatecancer are reported. The relative ability of the targeting group to bind to the human androgenreceptor was studied as a function of tether. The tether served to attach the antiandrogen tothe doxorubicin−formaldehyde conjugate via an N-Mannich base of a salicylamide derivative.The salicylamide was selected to serve as a trigger release mechanism to separate thedoxorubicin−formaldehyde conjugate from the targeting group after it has bound to theandrogen receptor. The remaining part of the tether consisted of a linear group that spannedfrom the 5-position of the salicylamide to the 3‘-position of cyanonilutamide. The structuresexplored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethyleneglycol), N,N‘-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of thetethers bound to the targeting group for human androgen receptor were measured using a3H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeteddrug with the butynediol-based linear region has a relative binding affinity of 10%. This relativebinding affinity is encouraging in light of the cocrystal structure of human androgen receptorligand binding domain bound to the steroid Metribolone which predicts very limited space fora tether connecting the antiandrogen on the inside to the cytotoxin on the outside.
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